Injury programs shape glioblastoma
Authors: Lucy J. Brooks, Holly Simpson Ragdale, Ciaran Scott Hill, Melanie Clements, Simona Parrinello
Journal: Trends in Neurosciences (2022)

Glioblastoma is a deadly brain cancer comprising cells that recapitulate normal neurodevelopmental lineage hierarchies.Increasing evidence suggests that injury responses superimpose onto these neurodevelopmental programs to fuel tumor heterogeneity and result from the growing tumor mass physically damaging the surrounding brain tissue, as well as from therapeutic intervention.Non-malignant cells within the normal brain tissue respond to tumor-induced injury by activating reactive programs, which in turn modulate glioblastoma biology.Tumor cells aberrantly mirror injury programs of their non-malignant counterparts by enacting latent reactive and regenerative responses.The interplay between neurodevelopmental and injury programs has therapeutic implications, and increased understanding of the molecular basis of these programs may lead to improved treatments. Glioblastoma is the most common and aggressive primary brain cancer in adults and is almost universally fatal due to its stark therapeutic resistance. During the past decade, although survival has not substantially improved, major advances have been made in our understanding of the underlying biology. It has become clear that these devastating tumors recapitulate features of neurodevelopmental hierarchies which are influenced by the microenvironment. Emerging evidence also highlights a prominent role for injury responses in steering cellular phenotypes and contributing to tumor heterogeneity. This review highlights how the interplay between injury and neurodevelopmental programs impacts on tumor growth, invasion, and treatment resistance, and discusses potential therapeutic considerations in view of these findings. Glioblastoma is the most common and aggressive primary brain cancer in adults and is almost universally fatal due to its stark therapeutic resistance. During the past decade, although survival has not substantially improved, major advances have been made in our understanding of the underlying biology. It has become clear that these devastating tumors recapitulate features of neurodevelopmental hierarchies which are influenced by the microenvironment. Emerging evidence also highlights a prominent role for injury responses in steering cellular phenotypes and contributing to tumor heterogeneity. This review highlights how the interplay between injury and neurodevelopmental programs impacts on tumor growth, invasion, and treatment resistance, and discusses potential therapeutic considerations in view of these findings. Glioblastoma (see Glossary) is the most common and aggressive primary brain cancer in adults, and is almost universally lethal with overall survival times among the worst of any cancer. 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One of the most prevalent patterns of transcriptional heterogeneity results from recapitulation of neurodevelopmental lineage hierarchies [7.Neftel C. et al.An integrative model of cellular states, plasticity, and genetics for glioblastoma.Cell. 2019; 178: 835-849Abstract Full Text Full Text PDF PubMed Scopus (617) Google Scholar,8.Couturier C.P. et al.Single-cell RNA-seq reveals that glioblastoma recapitulates a normal neurodevelopmental hierarchy.Nat. 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These lineage states exhibited by malignant cells are strongly influenced by the microenvironment in a region- and context-specific manner [6.Bhat K.P.L. et al.Mesenchymal differentiation mediated by NF-κB promotes radiation resistance in glioblastoma.Cancer Cell. 2013; 24: 331-346Abstract Full Text Full Text PDF PubMed Scopus (628) Google Scholar]. Recent evidence highlights a prominent role of injury responses as additional drivers of phenotypic heterogeneity [12.Richards L.M. et al.Gradient of developmental and injury response transcriptional states defines functional vulnerabilities underpinning glioblastoma heterogeneity.Nat. Cancer. 2021; 2: 157-173Crossref PubMed Scopus (42) Google Scholar, 13.Brooks L.J. et al.The white matter is a pro-differentiative niche for glioblastoma.Nat. Commun. 2021; 12: 2184Crossref PubMed Scopus (11) Google Scholar, 14.Wu Y. et al.Glioblastoma epigenome profiling identifies SOX10 as a master regulator of molecular tumour subtype.Nat. Commun. 2020; 11: 6434Crossref PubMed Scopus (13) Google Scholar] which result from damage caused by the growing tumor mass to the surrounding brain tissue via physical, ischemic, metabolic, neuroinflammatory, and neurotoxic insults [15.Seano G. et al.Solid stress in brain tumours causes neuronal loss and neurological dysfunction and can be reversed by lithium.Nat. Biomed. Eng. 2019; 3: 230-245Crossref PubMed Scopus (68) Google Scholar, 16.Lathia J.D. et al.Deadly teamwork: neural cancer stem cells and the tumor microenvironment.Cell Stem Cell. 2011; 8: 482-485Abstract Full Text Full Text PDF PubMed Scopus (180) Google Scholar, 17.Albulescu R. et al.Cytokine patterns in brain tumour progression.Mediat. Inflamm. 2013; 2013979748Crossref PubMed Scopus (106) Google Scholar, 18.Ye Z.C. Sontheimer H. Glioma cells release excitotoxic concentrations of glutamate.Cancer Res. 1999; 59: 4383-4391PubMed Google Scholar, 19.Ramírez-Expósito M.J. Martínez-Martos J.M. The delicate equilibrium between oxidants and antioxidants in brain glioma.Curr. Neuropharmacol. 2019; 17: 342Crossref PubMed Scopus (21) Google Scholar, 20.Travis Z.D. et al.Surgically-induced brain injury: where are we now?.Chinese Neurosurg. J. 2019; 5: 29Crossref PubMed Scopus (4) Google Scholar, 21.Okolie O. et al.Reactive astrocytes potentiate tumor aggressiveness in a murine glioma resection and recurrence model.Neuro Oncol. 2016; 18: 1622-1633Crossref PubMed Scopus (18) Google Scholar, 22.Turnquist C. et al.Radiation-induced brain injury: current concepts and therapeutic strategies targeting neuroinflammation.Neurooncol. Adv. 2020; 2vdaa057PubMed Google Scholar]. The interplay between neurodevelopmental and injury programs is emerging as an important factor impacting on treatment sensitivity [12.Richards L.M. et al.Gradient of developmental and injury response transcriptional states defines functional vulnerabilities underpinning glioblastoma heterogeneity.Nat. Cancer. 2021; 2: 157-173Crossref PubMed Scopus (42) Google Scholar]. In this review we describe how tissue injuries induced by developing tumors have two important consequences: (i) by eliciting injury responses in non-malignant cells, which feed back to shape tumor biology, and (ii) through the activation of similar albeit aberrant injury programs in tumor cells, which influence their malignant behavior. We explore the emerging concept that malignant cells respond to such injury cues by activating latent reactive and regenerative responses. Throughout we describe observations from both human and rodent studies. We highlight key outstanding questions and discuss how progress in our understanding of injury–tumor crosstalk may pave the way for greater insights into tumor biology, and ultimately translate to novel therapeutic applications. Single-cell analyses have demonstrated that, despite interpatient differences, intratumoral transcriptional patterns converge on a handful of hierarchically organized states that resemble normal neural lineages (Figure 1) [7.Neftel C. et al.An integrative model of cellular states, plasticity, and genetics for glioblastoma.Cell. 2019; 178: 835-849Abstract Full Text Full Text PDF PubMed Scopus (617) Google Scholar,8.Couturier C.P. et al.Single-cell RNA-seq reveals that glioblastoma recapitulates a normal neurodevelopmental hierarchy.Nat. Commun. 2020; 11: 3406Crossref PubMed Scopus (120) Google Scholar,23.Yuan J. et al.Single-cell transcriptome analysis of lineage diversity in high-grade glioma.Genome Med. 2018; 10: 57Crossref PubMed Scopus (85) Google Scholar]. These states are commonly referred to as oligodendrocyte progenitor cell-like (OPC-like), neural progenitor-like (NPC-like), astrocyte-like (AC-like), and mesenchymal-like (MES-like) [7.Neftel C. et al.An integrative model of cellular states, plasticity, and genetics for glioblastoma.Cell. 2019; 178: 835-849Abstract Full Text Full Text PDF PubMed Scopus (617) Google Scholar]. The MES-like state, although it does not resemble a normal neurodevelopmental phenotype, does show similarities to reactive astrocytes and will be discussed in detail later. It is important to note that these states are not discrete entities; instead, tumor cells display a continuum of 'differentiation' ranging from stem-like to more differentiated states, and exhibit plasticity between lineages [7.Neftel C. et al.An integrative model of cellular states, plasticity, and genetics for glioblastoma.Cell. 2019; 178: 835-849Abstract Full Text Full Text PDF PubMed Scopus (617) Google Scholar]. The presence of multilineage differentiation reflects the cellular origin of these tumors which are believed to derive mainly from neural stem cells (NSCs) or lineage-restricted progenitor cells such as OPCs [9.Lee J.H. et al.Human glioblastoma arises from subventricular zone cells with low-level driver mutations.Nature. 2018; 560: 243-247Crossref PubMed Scopus (281) Google Scholar,11.Liu C. et al.Mosaic analysis with double markers reveals tumor cell of origin in glioma.Cell. 2011; 146: 209-221Abstract Full Text Full Text PDF PubMed Scopus (438) Google Scholar,24.Zhu Y. et al.Early inactivation of p53 tumor suppressor gene cooperating with NF1 loss induces malignant astrocytoma.Cancer Cell. 2005; 8: 119-130Abstract Full Text Full Text PDF PubMed Scopus (403) Google Scholar]. In patients, low-level driver mutations have been observed in the subventricular zone (SVZ) of the brain, suggesting that, at least in some cases, tumors originate from this stem cell niche [9.Lee J.H. et al.Human glioblastoma arises from subventricular zone cells with low-level driver mutations.Nature. 2018; 560: 243-247Crossref PubMed Scopus (281) Google Scholar]. In support, functional studies in mice have shown that selective induction of somatic mutations in NSCs leads to tumorigenesis [10.Alcantara Llaguno S.R. et al.Adult lineage-restricted CNS progenitors specify distinct glioblastoma subtypes.Cancer Cell. 2015; 28: 429-440Abstract Full Text Full Text PDF PubMed Scopus (123) Google Scholar,11.Liu C. et al.Mosaic analysis with double markers reveals tumor cell of origin in glioma.Cell. 2011; 146: 209-221Abstract Full Text Full Text PDF PubMed Scopus (438) Google Scholar,25.Jiang Y. et al.Glioblastoma cell malignancy and drug sensitivity are affected by the cell of origin.Cell Rep. 2017; 18: 977-990Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar]. Although NSCs can give rise to tumors, in the normal brain they are outnumbered by OPCs, which exhibit a low level of proliferation throughout adulthood in humans [26.Geha S. et al.NG2+/Olig2+ cells are the major cycle-related cell population of the adult human normal brain.Brain Pathol. 2010; 20: 399-411Crossref PubMed Scopus (106) Google Scholar]. As such, OPCs also represent a prime candidate as cell-of-origin for glioblastoma. Indeed, the same genetic alterations that drive tumorigenesis in NSCs also give rise to tumors when induced specifically in OPCs in mice [10.Alcantara Llaguno S.R. et al.Adult lineage-restricted CNS progenitors specify distinct glioblastoma subtypes.Cancer Cell. 2015; 28: 429-440Abstract Full Text Full Text PDF PubMed Scopus (123) Google Scholar]. Moreover, p53/Nf1 deletion in NSCs has been shown to drive tumorigenesis through expansion of their OPC progeny [11.Liu C. et al.Mosaic analysis with double markers reveals tumor cell of origin in glioma.Cell. 2011; 146: 209-221Abstract Full Text Full Text PDF PubMed Scopus (438) Google Scholar]. Conversely, deletion of the same tumor suppressors in more mature cells of the neuronal lineage does not lead to tumor formation, indicating that the ability of these mutations to induce tumors declines with differentiation [27.Alcantara Llaguno S. et al.Cell-of-origin susceptibility to glioblastoma formation declines with neural lineage restriction.Nat. Neurosci. 2019; 22: 545-555Crossref PubMed Scopus (54) Google Scholar]. Although immature cell types are far more susceptible to malignant transformation, it is possible that tumors may also derive from mature cells in some circumstances. For example, p53 deletion in combination with overexpression of oncogenic Ras can drive tumorigenesis in cortical astrocytes [28.Friedmann-Morvinski D. et al.Dedifferentiation of neurons and astrocytes by oncogenes can induce gliomas in mice.Science. 2012; 338: 1080-1084Crossref PubMed Scopus (386) Google Scholar]. However, it should be noted that, although Ras signaling is frequently altered in glioblastoma, RAS mutations are uncommon [29.McLendon R. et al.Comprehensive genomic characterization defines human glioblastoma genes and core pathways.Nature. 2008; 455: 1061-1068Crossref PubMed Scopus (5698) Google Scholar]. The cell-of-origin may in part also influence the proportion of malignant cells that occupy the different lineage states within a tumor. In mice, identical tumorigenic stimuli induced in different stem/progenitor subpopulations produce markedly different glioma phenotypes, depending on the differentiation status of the transformed cell [25.Jiang Y. et al.Glioblastoma cell malignancy and drug sensitivity are affected by the cell of origin.Cell Rep. 2017; 18: 977-990Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar,30.Wang Z. et al.Cell lineage-based stratification for glioblastoma.Cancer Cell. 2020; 38: 366Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar]. Tumors derived from OPCs show an enrichment for expression of oligodendrocyte-lineage genes, whereas those derived from more immature GFAP+ NSCs have a greater capacity for self-renewal and shorter survival [10.Alcantara Llaguno S.R. et al.Adult lineage-restricted CNS progenitors specify distinct glioblastoma subtypes.Cancer Cell. 2015; 28: 429-440Abstract Full Text Full Text PDF PubMed Scopus (123) Google Scholar,25.Jiang Y. et al.Glioblastoma cell malignancy and drug sensitivity are affected by the cell of origin.Cell Rep. 2017; 18: 977-990Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar]. Although ascertaining the cell-of-origin in human glioblastoma is much more challenging, patient tumors show biases towards enrichment of transcriptional signatures associated with either an NSC or OPC cell-of-origin in mouse [30.Wang Z. et al.Cell lineage-based stratification for glioblastoma.Cancer Cell. 2020; 38: 366Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar]. In addition to cell-of-origin biases, the lineage trajectory of a cell is also influenced by somatic mutations [7.Neftel C. et al.An integrative model of cellular states, plasticity, and genetics for glioblastoma.Cell. 2019; 178: 835-849Abstract Full Text Full Text PDF PubMed Scopus (617) Google Scholar,13.Brooks L.J. et al.The white matter is a pro-differentiative niche for glioblastoma.Nat. 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Common alterations such as amplification of EGFR, PDGFR, or CDK4 can favorAC-like, OPC-like, or NPC-like states, respectively, whereas deletion of NF1 favors a MES-like state [7.Neftel C. et al.An integrative model of cellular states, plasticity, and genetics for glioblastoma.Cell. 2019; 178: 835-849Abstract Full Text Full Text PDF PubMed Scopus (617) Google Scholar,33.Wang Q. et al.Tumor evolution of glioma-intrinsic gene expression subtypes associates with immunological changes in the microenvironment.Cancer Cell. 2017; 32: 42-56Abstract Full Text Full Text PDF PubMed Scopus (711) Google Scholar]. However, although both cell-of-origin and genetic alterations bias cells towards a particular cell fate, genetic subclones comprise multiple phenotypes, indicating that non-genetic factors play a prominent role in determining cellular identity [7.Neftel C. et al.An integrative model of cellular states, plasticity, and genetics for glioblastoma.Cell. 2019; 178: 835-849Abstract Full Text Full Text PDF PubMed Scopus (617) Google Scholar]. In this regard, different tumor microenvironments have been shown to promote stemness or drive differentiation [13.Brooks L.J. et al.The white matter is a pro-differentiative niche for glioblastoma.Nat. Commun. 2021; 12: 2184Crossref PubMed Scopus (11) Google Scholar,31.Hara T. et al.Interactions between cancer cells and immune cells drive transitions to mesenchymal-like states in glioblastoma.Cancer Cell. 2021; 39: 779-792Abstract Full Text Full Text PDF PubMed Google Scholar, 32.Brooks L.J. Parrinello S. 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A prominent emerging feature of many of these microenvironments is the involvement of injury-associated processes which occur as a result of tumor expansion. Indeed, recent single-cell RNA sequencing (scRNA-seq) analyses of human glioblastoma found that injury-associated inflammatory and wound-response signatures account for much of the transcriptional heterogeneity in glioblastoma [12.Richards L.M. et al.Gradient of developmental and injury response transcriptional states defines functional vulnerabilities underpinning glioblastoma heterogeneity.Nat. Cancer. 2021; 2: 157-173Crossref PubMed Scopus (42) Google Scholar]. Furthermore, spatially separated injury-associated microenvironmental stimuli including hypoxia, immune infiltration, and white matter damage have all been implicated in steering cell fate, as determined by recent spatially resolved transcriptomic, metabolomic, and proteomic analyses, as well as by bulk RNA-seq or scRNA-seq from distinct tumor regions [13.Brooks L.J. et al.The white matter is a pro-differentiative niche for glioblastoma.Nat. Commun. 2021; 12: 2184Crossref PubMed Scopus (11) Google Scholar,37.Ravi V.M. et al.Spatially resolved multi-omics deciphers bidirectional tumor-host interdependence in glioblastoma.Cancer Cell. 2022; 40: 639-655Abstract Full Text Full Text PDF PubMed Google Scholar,38.Garcia-Diaz C. et al.Glioblastoma cell fate is differentially regulated by the microenvironments of the tumour bulk and infiltrative margin.bioRxiv. 2021; (Published online June 11, 2021)https://doi.org/10.1101/2021.06.11.447915Google Scholar] (Figure 1). These processes will be the focus of the following sections. Injury is a complex phenomenon driven by tissue damage, and involves a range of biological processes aimed at restoring tissue homeostasis. Injury of brain tissue encompasses insults ranging from traumatic brain injury (TBI), which causes stretching and tearing of axons and Wallerian degeneration [39.Koliatsos V.E. Alexandris A.S. Wallerian degeneration as a therapeutic target in traumatic brain injury.Curr. Opin. Neurol. 2019; 32: 786-795Crossref PubMed Scopus (13) Google Scholar], to ischemia, which occurs when blood flow and oxygenation do not meet demand, leading to metabolic collapse and cell death [40.Kalogeris T. et al.Cell biology of ischemia/reperfusion injury.Int. Rev. Cell Mol. Biol. 2012; 298: 229Crossref PubMed Scopus (1235) Google Scholar]. 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Eng. 2019; 3: 230-245Crossref PubMed Scopus (68) Google Scholar], and/or by inducing hypoxia/nutrient stress [16.Lathia J.D. et al.Deadly teamwork: neural cancer stem cells and the tumor microenvironment.Cell Stem Cell. 2011; 8: 482-485Abstract Full Text Full Text PDF PubMed Scopus (180) Google Scholar] and releasing tumor-derived factors, which include toxic levels of cytokines [17.Albulescu R. et al.Cytokine patterns in brain tumour progression.Mediat. Inflamm. 2013; 2013979748Crossref PubMed Scopus (106) Google Scholar], glutamate [18.Ye Z.C. Sontheimer H. Glioma cells release excitotoxic concentrations of glutamate.Cancer Res. 1999; 59: 4383-4391PubMed Google Scholar], and free radicals [19.Ramírez-Expósito M.J. Martínez-Martos J.M. The delicate equilibrium between oxidants and antioxidants in brain glioma.Curr. Neuropharmacol. 2019; 17: 342Crossref PubMed Scopus (21) Google Scholar] (Figure 2). In addition, standard-of-care treatments also induce forms of injury [20.Travis Z.D. et al.Surgically-induced brain injury: where are we now?.Chinese Neurosurg. J. 2019; 5: 29Crossref PubMed Scopus (4) Google Scholar, 21.Okolie O. et al.Reactive astrocytes potentiate tumor aggressiveness in a murine glioma resection and recurrence model.Neuro Oncol. 2016; 18: 1622-1633Crossref PubMed Scopus (18) Google Scholar, 22.Turnquist C. et al.Radiation-induced brain injury: current concepts and therapeutic strategies targeting neuroinflammation.Neurooncol. Adv. 2020; 2vdaa057PubMed Google Scholar]. For example, surgical brain injury is an unavoidable aspect of tumor resection because of the nature of neurosurgical maneuvers which involve incision and electrocauterization of brain tissue [20.Travis Z.D. et al.Surgically-induced brain injury: where are we now?.Chinese Neurosurg. 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